Note: Descriptions are shown in the official language in which they were submitted.
33~1~
Related Application: Related hereto is Canadian Patent
Application Serial No. 374,487, filed on the same date as
this application.
mis invention relates to a process for preparing
N-[(l-naphthalenyl)thioxomethyl]glycine derivatives.
Background o-f the Invention
The N-[(l-naphthalenyl)thioxomethyl]glycine
derivatives, produced by the process disclosed herein,
are inhibitors of aldose reductase. Accordingly, the
derivatives are useful for treating diabetic complications,
for example, neurophaty, nephropathy, retinopathy, cataracts
and atherosclerosis.
The derivatives, and another process for preparing
them, are disclosed in Canadian Patent Application Serial
No. 372,119. According to that process, the derivatives are
prepared by coupling a carboxyl activated derivative oE an
appropriate l-naphthalenecarboxylic acid with a glycine ester
to obtain the corresponding N-[(l-naphthalenyl)carbonyl~
~lycine ester, reacting the latter compouncl with phosphorus
pentasulfide to obtain the corresponding ~-[(l-naphthalenyl3
thioxomethyl]glycine ester, and then hydrolyzing the last-
named compound to obtain the desired corresponding acid.
Optionally, the order of the last two steps can be reversed.
The present process has the advantage over that
just described in that the process hereof provides the
~-[(l-naphthalenyl)thioxomethyl]glycine derivatives directly
from precursors having a preformed thioamide portion. More
explicitly, according to the process of thi~s invention, the
~-[(l-naphthalenyl)thioxomethyl]glycine derivatives are
obtained by thionaphtholylation o~ the appropriate aminoacid
by using either a (naphthalenylthioxomethylthio)acetic acid
or a naphthalenedithioic acid as the agent. Although thio-
benzoylation reaction of aminoacids have been reported, for
example, see A. Lawson and C.E. Searle, J. Chem. Soc., 1556
(1957), M.A. Elgendy et al., Bull. Faculty o-f Pharmacy, Cairo
University, 12, 165 (1975) and A. Kjaer, Acta Chem. Scand.,
3~2
- la -
4, 1347 (1950), thionaphthoylation reactions of the type
di.sclosed herein apparently are novel and allow the
preparation of pharmaceutical]y useful compounds by a
simple, direct process which avoids the use of expensive
or obnoxious chemicals or the need of protecting groups.
3~
-2- AHP-7840
Sum m ~ ,~b3~
A process is provided for preparing N~[(l-naphthalenyl)thioxomethyl~-
glycine derivatives of formula I
S S-C-N(Rl)-C}12COOlI
I
~ (I)
,~
R3
R2
in which Rl is lower alkyl, R2 is hydrogen, lower alkyl, lower alkoxy, halo or
trifluoromethyl and R is hydrogen, lower alkyl, lower alkoxy or trifluoromethyl, S which comprises:
a) reacting7 uncler neutral or alk~line conditions, the compound
of formula 11
S-(j-S~ Y ~
2~) R3'/~ tII)
in which R2 and 1~ are as defined herein and Y is Mg-(complex), Li, NQ or K;
25 with the proviso that when Y is Mg-(complex) or Li then R2 is other than bromo,
chloro or iodo, with a haloacetic acid to obtain the corresponding compound
of formula Ill S-F-SCH2COOH
~III)
R
in which R2 and R3 are as defined herein; alld coupling, under neutral or alkallne
conditions, the compound of formula 111 with Qn aminoacid of the formula HN(R
CH2COOH in which Rl is lower alkyl; or
33~
~3- AHP-7840
b) reacting the compound of formula II, as defined above, with an
aminoacid of the formula HN(Rl~CH2COOf-l in which Rl is lower alkyl under
neutral or alk~line conditions.
S In a preferred embodiment of this process Rl is methyl7 R2 is hydrogen,
bromo7 chloro or trifluoromethyl, and R3 is hydrogen or methoxy.
Detailed Descri~tion OI the Invention
The term 'qower alkyl" as used herein means a straight chain alkyl
radical containing from one to four carbon atoms or a branched chain alkyl
radical containing three or four carbon atoms and includes methyl, ethyl, propyl,
I-methylethy], butyl, 2-methylpropyl and l,l-dimethylethyl. Preferred lower
~lkyl radieals contain one to three carbon atoms.
The term 'qower alkoxy" or 'qower alkoxide" as used herein means
a straight`chain alkoxy radical containing from one to six carbon atoms, pre-
ferably one to three carbon atoms, or a branched chflin alkoxy radical containing
three or four carbon atoms, and includes methoxy, ethoxy, l-methylethoxy,
butoxy and hexanoxy.
The term "halo" as used herein rneans a halo radical and includes,
fluoro, chloro, bromo and iodo.
The term '~ower alkanol" as used herein means a straight chain alkanol
contAining one to four carbon atoms or a branched chain alkanol containing
three or four carbon atoms and includes methanol, ethanol9 propanol, l-methyl-
bromo and iodo.
The term l'neutral conditions" as used herein means a reaction medium
having a p~ of nbout 7. Thus, if a reactant being employe~ in the medium h~s
an acidic function, then sufficient base, pre~erably an alkali metal, alkaline
earth metal hydroxide or carbonate, is present in the medium to e~fect the
neutralization of the acidic function.
The term "alkaline conditions" as used herein means conditions wherein
3() a strong base is employed in the presence of water as the principal pH controlling
agent to maintain the pH of the reaction medium above pH 7. Suitable strong
bases includes the hydroxides or carbonates of the alkRli metal or alkaline earth
metals for instance, sodium, potassium, magnesium or calcium and the like.
Suitable solvents for the reations medium are water or a mixture of water and
a water-miscible solvent; for example, the lower alkanols, tetrehydrofuran
or dioxane~
3~2~
4- AHP-7840
The term "Mg-(complex)" RS used herein refers to the cation portion
of an aryldithioic Qcid salt obtained as the reaction product of hn aPylmagnesium
halide with carbon disulfide, the product being ~ aryldithioic acid-magnesium
5 hali de salt.
The starting material of formula Il, a l-naphtllalenedithioic acid
salt, can be prepared as illustrated by the following scheme.
1() ~ ~ ~\5~
~2 (:[V) 2) CS
~H2X R3 ~
'~ R (II)
alkali metal lower alkoxide
1~2 (V~
2() More specifically, the starting mat~erial of formula II in which R2
alld R3 Rre AS defined herein, with the proviso that R2 is other than bromo,
chloro or iodo, and Y is Mg-(complex) or Li can be prepared by reacting the
l-lullorlnphthalene: derivative of formula IY in which R2 and R3 are as cle~inedin the last instnnce ~nd X is bromo, chloro or iodo with magnesiurn or lithium
~s metal to obtain the corresponding Grignard reagetlt or aryllithium derivative,
respectively. Reaction of the Grignard reagent or the corresponding aryllithium
derivative with carbon disulfide affords the compound of formula Il in whie~h
R2 and R3 are as defined in the last instance and Y is Mg~complex) or Li~
Convenient conditions for effecting the preceding reaction include
30 the use of one to five molar equivalents of earbon disulfide, ~ re~ction tempera-
ture ranging from -10 to 25 C and a reaction time ran~ing from 30 minutes
to 24 hours.
The requisite l-haloderivatives of formula IV are known or can be
prepared by known methodsO For example, see "Elsevier's Encyclopaedia o
35 Organic Chemistryt', F. Radt, ~d., Series Ill, vol l~B, Elsevier Publishing Co.,
Amsterdam, 1953, pp 264-321.
2~
~5~ AHP-7840
Alternatively, the l-(h~lomethyl)-naphthalene derivative OI formula
V wherein X is bromo7 chloro or iodo ~nd R2 and R are as defined in ~he first
instance can be reacted with elemental sulfur in the presence of an alkali metal(lower)alkoxide, for instance sodium or pota~sium methoxide, to give the corres-
5 ponding l-naphthalenedithioic acid of formula Il in which R2 and R3 ~re as defined
in the latter is~stance and Y is a cation derived from the alkali metal (lower~
alkoxide.
The requisite l-(halomethyl)-naphthalene derivatives of formula
V are known or can be prepared by known methods. For example, see "Elsevier's
1() Encyclop~edia of Organic Chemistry", cited nbove, pp 241-263.
Thereafter, the compound of formula 11 in which R and R3 are
as defined herein and Y is Mg-(complex), Li, Na or K, with the proviso that
when Y is Mg-(ccmplex~ or Li then R2 is other than bromo9 chloro or iodo9 is
reacted under neutral or alk line conditions with a haloacetic acid to give the
15 corresponding compound of formula III.
Convenient and practical conditions for the latter reaction comprise
reacting the compound of formula 11 with bromoacetic acid or chloroacetic
acid in an aqueous medium in the presence of a sufficient amount of an alkali
or alkaline earth metal hydroxide or carbonate, preferably sodium hydroxide
2() or sodium carbonate, to convert the haloacetic acid to its corresponding salt.
Preferrnbly, 1.0 to 1.2 equivalents of the alkali or alkaline earth hydroxide orcarbo~ te is employed. R~action temperature~s and times range from -10 to
25 C and 6 to 72 hours, respectively~ Thereafter, the reaction mixtur~ is
rendered acidie, for example, by the addition of a mineral acid9 for instance,
25 hydrochloric acid or sulfuric acid; and the product~ i.e. the compound of formula
III, is isolated by extraction or filtration.
Subsequent coupling cf the compound of formula III in which R2
and R3 are as defined herein with the aminoacid of formula HN(Rl~CH2COOH
under allcaline conditions give the corresponding N~ naphthalenyl~thioxomethyl]-
30 glycine derivative of formula 1.
~.
3~
-6 AHP-7840
A convenient and practieal mode for effecting the coupling reaction
comprises dissolving separately the compound of forrnula III and the amino~cid
in water containing at least one equivalent amo~u~t of a hydroxide or carbonate
s of fln alkali or alkaline earth me-lal so that each compound is in the form of
R salt; mixing the two solutions together; and keeping the mixture at 10 to 80 C,
preferably 20 to 25~ C, for 2 to 7 days, or until the reaction is complete as
indicated by thin layer chromatography (tlc). Subsequently, the reaction mixtureis madc acidic with a mineral acid and the desired product, the eompound of
formula 1, is isolated by filtration or extraction.
Alternatively, the cornpound of formula I can be obtained in a one-
step reaction by reacting the compound of formula II in which lR2, R3 and Y
are as defined herein with the aminoacid of formula HN(Rl)-CH2COOH under
neutral or alkaline conditions, namely in the presence of at least one equivalent
amount of a strong base so that the aminoacid is in the form of its base addition
salt.
An efficient and practical way of effecting this latter reaction in~
cludes the use of one to two molar equivalents of arl ~lkali metal or earth alkaline
metal hydroxide or carbonate, preferably sodium hydroxide or sodium carbonate,
as the strong bas~, water as the reaction solvent, and reaction temperatures
and times rangin~ from 10 to 100 C, preferably 20 to 80 C, and 2 to 7 days,
or until the reaction is complete as indicated by tlc.
The foUowing examples further illustrate this invention.
~XAM PLX 1
[1~5-Bromo-l-riaphthalenyl)thioxomethyl] thio] acetic Acid (III, E~ = Br and R3 = H)
A solution o~ 1,5-dibromonaphthalene ~3.58 g~ 12.5 mmoles9 described
by G. Chatelain, Comm. Energic A.t. (France), Rappt. CEA-R-2858 (1965), see
Chem. Abstr., 65,13626, and by H.H. Hodgson and J.S. Whitellurst, J. Chem.
Soc., 80 (1947)~ ,192-dibromoet}ldne (0.1~ ml, 2.1 mmoles) in freshly dlstilled,anhydrous tetrshydl of uran was added over a period of 2 min to finely cut m~g
nesium ribbon (35S mg, 14.7 mmoles) under a nitrogen atmosphere. The exothermic
reaction was complete in 20 min. The re~ction mixture was stirred for an additional
0.5 hr. This solution OI l~bromo-5-naphthalenylmagnesiusn bromide was trans-
ferred under nitrogen to a dropping funnel inserted in a 3 necked flask containing
carbon disulfide (1.17 ml, 19.9 mmoles) in dry diethyl ether (7 ml~ under a nitrogen
3~
~ 7~ A.HP-7B40
atmosphere. The carbon disulfide solution was cooled to -5 C by immersing
the 3-necked flask in an acetone-ice bath~ The Grignard reagent solution was
added dropwise with efficient stirring while maintaining the temperatlJPe o~
the renction mixture at -5 C. The reaction mixture was allowed to come to
room temperature (20-22 C) over 18 hr. The stirred reaction mixture was cooled
in an ice bath and decomposed by the addition of lû g of ice, followed by the
addition OI 20 ml of water. This mixture was filtered to remove the insoluble
material. Diethyl ether (20 ml) w~s added to the filtrate and the mixture was
shaken. The aqueous layer9 containing (5-bromo-1-naphthalelle)dithioic ~cid
in the form of a complex magnesium salt, was separated and Mdded to a solution
of chloroacetic acid (1.18 g, 12.15 mmoles) in water (7 ml) neutralized with sodium
carbonate (0.7 g, 6.5 mmoles). The resulting red solution was allowed to stand
for 48 hr at 5 C. The reaction mixture was then made acidie by adding a solution
of concentrated sulfuric acid (0.8 ml) in water (2 ml). The product was extracted
with methylene chloride (2X) and the organic layer was washed with water (4X)
and dried (Mg,SO~l). Evaporation of solvent afforded the ~rude title compound
ta.o2 g) as an or~nge semi-solid. The semi-solicl was crystallized from a mixture
of benzene ~d hexane to give l.l g of the title eompound; mp 137 -139 C; NMR
2() (CDC13) ~ 4.35 (s, 2H), 7.7 (m, 6H), 9.9 (broad, lH); IR (CHC13) 2900,1715 cm 1
EXAMPLE 2
[[(l-Naphthalenyl)thioxomethyl~ thio] acetic Acid ~ R2 and R3 = H)
l-(Chloromethyl)naphthalene [1.76, llD mmoles, describe~ by H.W.
Coles and M.L. Dodds, J. Am. Chem. Soc., 60, 853 (1938)1 was added dropwise
to a well stirred mixture of sulfur (640 rng) and sodium methoxide (1.1 g, 20
mmoles) in dry methanol (10 ml). The mixture was refluxed for 18 hr, cooled
to 20 - 22 C and the volatile portion removed by distillat;on under reduoed
pressure. The residue was dissolved in water (5 ml). A small amount of insolublematerial suspended in the solution was removed by filtration. The clarified
solution, containing the sodium salt of (l-naphthalene)dithioic acid, was added
to a solution of chloroacetic acid (3O2g~7 30 mmoles) and sodium carborlate (3.28
g, 31 mmoles~ in water (5 ml). The mia~ture was kept at 5 C for 2 days, adjusted
to pH 3 with lN aqueous HCl and extracted with EtOAc. The extract was washed
with water, dried (MgSO4) and concentrated to dryness under reduced pressure.
3~
-8- AHP-7840
The residue was crystRllized from benzene to give the title compo~md as red
crystals; mp 134 -137 C; NMR (CDC13) ~ 4.35 (s, 2H), 7.7 (m, 7H~, 10.5 (broad,
lH); UV ~ max (EtVH) 306 nm ( ~ 9,970), 219 (65,890).
EXAMPL~ 3
N-[(5-Brom~l-naphthalenyl~thioxomethyl]-N-methylglycine (I, Rl - CH3, R2 =
Br and R3 = H)
To a suspension of [[(5-brom~l-mlphthalenyl)thioxomethyl] thiol acetic
acid (500 mg, 1.47 mmoles, described in example 1) in lN aqueous NaOH solution
(1.8 ml, 1.8 mmoles), a solution of N-methylglycine (157 mg, 1.76 mmoles) in
lN aqueous NaOfl (2.1 ml, 2.1 mmoles) wns added. 'I`he mixtllre was heated at
70 C for 7 days. The reaction mixture was cooled and filtered. The filtrate
was diluted with water (10 ml) and washed twice with chloroform~ The aqueous
phase was made ecidic with concentrated HCl and extracted with chloroform.
The latter chloroform extract was washed with water, dried (MgSO4) and evapo~
rated to clryness. The residue was cryst~llized from a mixture of benzene and
hexane to give 55 mg of the title compound; mp 174 - 175 C; NMR (CJ)C13)
2.95 (s, 3H), 4.65 ~ 5.18 (2d, J = 16.5 HZ! 2H), 7.2-8.2 (m, 6H); IlR (Nujol* )
2900, 1715 cm 1; UV ~ max (EtOH) 280 nm ( ~13,200), 219 (50,600).
EXAMPLE 4
N-[(l-Naphthalenyl)thioxomethyl~-N-methylglycine (I, R1 - CH3 and R2 and
R3 = M)
Procedure 1~:
A solution of N-methylglycine t0.4 g, 4.5 rnmoles) in 2N aqueous
NaOH (2-7 ml, 1.2 equivalents) w~s added to a stirred cooled solution of ~
naphthalenyl3thioxomethyl] thio] acetic acid (0.65 g, 2.5 mmoles, described in
example 2~ in 2N aqueous NaOH (1.27 ml, 1 equivalent). Water (4 ml) was added
to the mixture until a clear red solution was obtained. The solutîon was heated
at 70 C until the disappearance of the starting material was noted by thin
layer chromatography (10% MeOH in CHC13, silica gel) after about 12 hr. After
cooling to ice-bath temperature, the solution was made acidic with 3N aqueous
HCl. The resulting mixture was extracted with ethyl acetate. The extract
was washed with water, dried (MgSO,~) and concentrated under reduced pressure.
The residue was crystallized from toluene. The crystals were ~olleeted~ washed
with cold toluene and dried in high v~cuum to give 150 mg of the title compound;
* Nujol is a trademark for a brand of white mineral oil
33~
9~ AHP-7840
mp 145 -148 C; NMR (CD(:13) ~ 3.05 (s, 3H), 4.75-5.3n (d, J = 17.5Hz, 2H), 7.30-
7.90 (m, 7H), 8.85 (broad, lH); IR (CHC13) 3000,1720 (~vith infle~tion at 1755)
cm
Procedure B:
l-(Chloromethyl)naphthalene (3.52 ~, 20 mmoles) w~s added dro~
wise to a well stirred mixture of sulfur ~1.28 g, 40 mmoles) and sodlum methoxide
(2.2 g, 40 mmoles) in dry methanol (20 ml). The mixture was refluxed for 18
hr. The reddish mixture was cooled to 2û - 22 C and the ~olatile part of the
1 () mixture w~s removed by distillation under reduced pressure. The residue, ~on-
taining the sodium sall of (l-naphthalene)dithioic acid, was dissolved in water
(10 ml) and added to a solution of N-methylglycine (3.6 g, 40 mmoles) in 4N
aqueous NaOH (10.5 ml). The solution was stirred ~t 20 - 2~ C for 18 hr; ~t
70 C for 8hr; ~nd finally at 20 - 22~ C for 3 days. The mixture vvas extracted
with ethyl acet~te. The pH of the a~ueous layer w~s adjusted to 3 with lN ~queous
HCl. 'I'he aqueous phase was extracted with ethyl acetate. The extract was
washed with water, dried (MgSO~,~) and concentrated to dryness under reduced
pressure. The residue was crystallized twice from toluene to give 130 mg oî
the title compound, identical to the product of procedure A of this exMmple.
By following serially the procedures of examples 1 or 2 ~nd 3 or
4 (Procedure A), or by following the procedure of example 4 (Procedure B),
and using the appropriate reactants, other (ornpounds of formul~ I are obtained.For example, by following serially the procedllres of examples I and 3 and replacing
l,S~dibromonaphthalene with an equi~alent amount of S-bromo-l-methoxynaphtha-
lene, N-~t5-methoxy-1-naphth~lenyllthioxomethyl3glycine~ mp 120C, NMR
(DMSO-d6) ~ ?.93 (S, 3H), 3.90 (s, 3H), 4.65 & 5.16 (2d, J ~ lz, 2H)9 6~95
(2d, Jl = 7Hz, J2 = 3Hz, lH), 7.35 (m, 4H3, 8.11 (2d, 31 = 8Hz, J2 - 2Hz, lH~, was
obtained; by following serially the procedures of ex~mples 1 arld 3 and replacing
1,5-dibromonaphthalene with an equivalent amount of 175-dichloronaphthalen~,
N-[(5-chloro-1-n~phthalenyl)thioxomethyl] glycine, mp 153 - 154 C, NMR (CDC13)
~ 3.03 (s, 3~ SD67 ~k 5.33 (d, J = 17Hz, 2H), was obtainedi by ~ollowing serially
the procedures of examples 1 and 3 and replacirlg 1,5 dibromonaphthalene with
an equivalent amount of 5-brom~l-methylnaphthalene, N-[(5-methyl-l~naphtha-
lenyl)thioxomethyl]-N-methylglycine, mp 190 -191 C, NMR tCDC13) ~ 2.66
(s, 3H), 3.05 (s, 3H~, 3.85 ~ 5.0 (m, 2H), 7.5 (m 6H), 8.75 ~bro~d, lH3, was obta;hed;
-10- AHP-78~0
by following serially the procedures of examples 2 and 4 (procedure A) or by
following proeedure B of example 4 and replacing l-(chloromethyl)naphthalene
with an equivalent amount of l-(bromomethyl)-5-bromo-6-metholcynaæhthalene,
N-[(5-bromo-6-methoxy l-naphthalenyl)thioxomethyl] N-methylglycine; mp
166 -168 C, NMR (CDC13~ 3.02 (s, 3H), 4.06 (s, 3H)9 4.61 & 5.39 (d, J -17Hz,
2H), was obtained and by following serially the procedures of examples 2 and
4 (procedure A), or by following the procedure B of example 4 and replacing
l-(chloromethyl)naphthalene with an equivalent amount of l-(chloromethyl)-
l 0 5-(trifluoromethyl)-6-methoxyne~phthalene, N-1[(5-trifluoromethyl)-6-methoxy-
1-naphthalenyl] thioxomethyl] -N-methylglycine, mp 164 -165 C, NMR (CDC13)
3.05 (s, 3H), 3.95 (s, 3H), 4.55 ~c 5.4 (d, J = 17HZ, 2H), 7.6 (m, SH), 9.8 tbroad,
lH), was obtained.
EXAMPLE 5
The aldose reductase inhibiting effects of the compounds of formul~
I can be demonstrated by employing an in vitro testing procedure similar to
that described by S. Hayman and J.H. Kinoshita, J. Biol. Chem., 240, 877 (1965).In the present case the procedure of Hayman anld Rinoshita i5 modified in that
the final chromatography step is omitted in the preparation of the enzyme from
bovine lens.
The following results were obtaineld when the îoregoing listed com-
pound of for mula I were evaluated in the above in vitro test.
Q3;2~
HP-7840
% Inhibitlon at
Different Molar
Concentrations
(in vitro)
Test Compound lO S lo-6 10-7
N-[(5-brom~l-naphthalenyl)thioxomethyl] -
N-m ethylglycine 93 ~7 47
I()
N-1(5-methoxy-l-naphthalenyl)thioxomethyl3 -
N-methylglycine 83 64 17
N-[(5-chloro-l-naphthalenyl)thioxomethyl] -
N-methylglycine 88 75 29
N-[(5-m ethyl-l-naphthalenyl)thioxomethyl] -
N-methylglycine 8'd 74 26
2() N-~(5-bromo-6-methoxy-l-naphthalenyl)-
thioxomethyl]-N-methylglyoine 99 91 72
N[[(5-trifluoromethyl)-6-methoxy~
n~phthalenyl] thioxomethyl]-N-methylglycine 98 94 65
The N-1(1-n~phth~lenyl)thioxomethyl] gly~ine deriv~tives of formul~
I can be administered to mammals, for example, m~n, cattle or rabbits, either
alone or in dosage forms, i.e., capsules or tablets, combined with ph~rmacologically
acceptable excipients, see below. Advanta~eously, the compounds of formula
I are given orQlly. They m~y be administered orally in solid form containing such
30 excipients as starch, milk sugar, certain types of clay and S3 forth. They may
also be administered orALly in the form of solutions or they may be injected pa-renterally. For parenteral administration they rnay be used in t;le forrn of ~ sterile
solution, preferably of pH 702 - 7.6, containing a pharmaceutically ~cceptable
buffer.
-12- AHP-7840
The dosage of the compound of formula I will vary with the form of
adrninistration and the particular compound chosen. Furthermore, it will vary
with the particular host under treatmerllt. Generally, treatment is initiated with
5 small dosages substantislly less than the optimal dose of the cornpound. Ther~after the dosage is increased by smnll increments until effi~acy is obtained. Ingeneral, the compounds of formula [ are most desirably administered at a concen-tration level that will generally afford effective results without causing arly harmful
or deleterious side effects. For topieal administration a 0.05 - 0~2% solution may
be administered dropwise to the eye. The frequency of instillation varies with
the subject under treatment from a drop every two or three dsys to once daily.
For oral or parenteral administration a preferred level of dosage ranges from
about 0.1 mg to about 200 mg per kilo of body weight per day, although aforemen-tioned variations will occur. However, a dosage level that is in the range of from
15 about 0.5 mg to about 30 mg per kilo of body weight per day is most satisfactory.
Unit dosage forms such QS capsules, tablets, pills and the like may
contain from nbout 5.0 to about 250 mg of the compounds of ~ormula 1, preferablywith a significant quantity of a pharma~eutical carrier. Thus, for oral admin-
istratiorl, capsules can contain from between about 5.0 to Rbout 250 mg of the
2(J active ingredients with or without a pharmaceutical diluent. Tablets, eithereffervescent or noneffervescent, can contain bletween about 5.0 to 250 mg of
the active ingredients together with conventional pharmaceutical carriers. Thus,tablets which may be coated ancl either effervescent or noneffervescent may
be prepared ac~ording to the l<nown art. Inert diluents or carriers, for example,
25 magnesium carbonate or lactose, can be used together with conventional disint~
grating agents for example, magnesium stearate.
Syrups or elixirs suitable Ior oral aclministrQtion can be prepared from
water soluble salts, for example, sodium N-~[5-(trifluoromethyl)-6-methoxy-1-naphtha-
lenyl] thioxomethyl]-N-methylglycinate, and may sdvantageously contain glycerol
30 and ethyl alcohol as solvents or preservatives.
